This dataset records Cladophora and associated benthic algae, collectively Cladophora community or submerged aquatic vegetation (SAV), biomass collected during the growing season of 2021 at stations located along the U.S. shoreline of Lakes Michigan, Huron, Erie, and Ontario. It also records a variety of supporting data collected at Cladophora measurement stations. These supporting data include: - seasonal time series of light, currents, wave action, temperature, specific conductivity, turbidity, pH, phycocyanin, chlorophyll, and dissolved oxygen from moored sensors at a subset of stations; - measurements of Secchi disk depth and water chemistry; - water column profiles of PAR, temperature, specific conductivity, turbidity, pH, phycocyanin, chlorophyll, and dissolved oxygen; - diver observations of SAV, dreissenid mussels, round goby abundance, and substrate properties; - measurements of dreissenid mussel abundance and size class distribution coincident with SAV biomass; - nutrient content of SAV, dreissenid mussels, and sediments; - and information about sampling locations and operations. Similar data were collected at several of the same transects within four Great Lakes in 2018, 2019, and 2020 are available at (2018) https://doi.org/10.5066/P9E570JS, (2019) https://doi.org/10.5066/P99O4QXB, and (2020) https://doi.org/10.5066/P9O9FSTT.